Intraoperative and external beam irradiation +/- 5-FU for locally advanced pancreatic cancer

Because of the poor local control rates obtained with external beam irradiation +/- chemotherapy for locally advanced pancreatic cancer, our institution has used intraoperative radiation therapy (IORT) with electrons to deliver a single "boost" dose of radiation in 52 patients with biopsy-proven adenocarcinoma (primary, unresectable-49; primary, residual-2; and recurrent, unresectable-1). Patients received 4500-5000 rad of fractionated external beam irradiation and an IORT dose of 1750 rad (2 patients) or 2000 rad (50 patients). Acute and chronic tolerance have been acceptable. Documented local progression within either the external beam or IORT fields has been infrequent (3 of 42 evaluable patients or 7%), but there has been little, if any, change in median or long-term survival from that seen in external beam series. This is probably because of a high incidence of liver and peritoneal metastases with pancreatic cancer. A phase II pilot trial, which combines upper or total abdominal irradiation and infusion 5-FU with tumor nodal irradiation plus IORT, is in progress in our institution to evaluate tolerance and the relative incidence of abdominal failures.     

Intraoperative electron beam radiation therapy for recurrent locally advanced rectal or rectosigmoid carcinoma

A multimodality approach of moderate-dose to high-dose preoperative radiation therapy, surgical resection, and intraoperative electron beam radiation therapy (IORT) has been used for patients with locally recurrent rectal or rectosigmoid carcinoma. The 5-year actuarial local control and disease-free survival for 30 patients undergoing this treatment program were 26% and 19%, respectively. The most important factor predicting a favorable outcome was complete resection with negative pathologic resection margins. The determinant local control and disease-free survival for 13 patients undergoing complete resection were 62% and 54%, respectively, whereas for 17 patients undergoing partial resection these figures were 18% and 6%, respectively. There did not appear to be a difference in local control or survival based on the original surgical resection (abdominoperineal resection versus low anterior resection). However, the likelihood of obtaining a complete resection after preoperative radiation therapy was higher in patients who had previously undergone a low anterior resection than patients undergoing prior abdominoperineal resection. For the 30 patients undergoing external beam irradiation, resection, and IORT, the most significant toxicities were soft tissue or sacral injury and pelvic neuropathy. Efforts to further improve local control are directed toward the concurrent use of chemotherapy (5-fluorouracil with and without leucovorin) as radiation dose modifiers during external beam irradiation and the use of additional postoperative radiation therapy.     

The role of misonidazole combined with intraoperative radiation therapy in the treatment of pancreatic carcinoma

We tested the efficacy of the hypoxic cell sensitizer misonidazole in conjunction with intraoperative electron beam radiation therapy (IORT) and external beam irradiation in patients with locally advanced, nonmetastatic adenocarcinoma of the pancreas. Misonidazole was delivered intravenously (IV) at a dose of 3.5 g/m2 in conjunction with IORT of 1,500 to 2,000 cGy to the pancreas. Additional external beam radiation as administered to 4,960 cGy. The study was based on the premise that the effect of misonidazole would be maximized when a high dose of the drug was administered and, thus, high hypoxic cell sensitization could be obtained when using a high single dose of radiation where the hypoxic fraction would be expected to dominate in the survivors. In a nonrandomized study of 41 patients treated with misonidazole and 22 without, the 1-year local control was 67% and 55%, and 1-year survival was 50% and 77%, respectively. Although there was a bias towards larger tumors in the patients treated with the sensitizer, we were unable to demonstrate an advantage to misonidazole in this clinical situation.     

Intraoperative radiation therapy in the multimodality approach to upper aerodigestive tract cancer

The cure rate of operable lung cancer and locally advanced head and neck cancer remains suboptimal, with a limited rate of local control despite improvements in the surgical removal of primary tumors and in methods for mediastinal lymph node dissection, in particular. The efficacy of adjuvant therapy, such as EBRT, has improved, and the immediate efficacy of new chemotherapeutic drugs is increasingly significant, although local recurrences remain frequent. Locoregional failure is not uncommon in upper aerodigestive tract cancers. Factors limiting radiocurability for locally advanced (stage III) lung cancer include mediastinal intolerance of irradiation (high risk of mediastinal fibrosis, which increases exponentially when levels of much more than 50 Gy are administered to the whole mediastinum) and the very high radiosensitivity of the healthy lung, which can develop fibrosis with relatively small or moderate doses starting at 18 to 20 Gy, and even more frequently when larger volumes are irradiated. Head and neck neoplasms are less difficult sites in which to administer doses of up to 70 Gy of external beam radiotherapy initially, but, like locoregionally recurrent lung cancers, they are not easily reirradiated with tumoricidal doses of EBRT. For these reasons, IORT seems to be a good option for increasing local control, because areas of [figure: see text] residual microscopic disease may be irradiated using IOERT approaches without affecting critical organs to the same extent. In addition, careful patient selection is paramount. Combined modality treatment regimens incorporating IORT may benefit patients with locally advanced disease. The ability of IORT to sterilize microscopic residual disease can enhance the "completeness" of resection and thus, theoretically, improve local control. Although distant disease dissemination remains by far the overriding issue, as newer effective agents emerge, local failure will continue to be a problem. Preliminary studies have demonstrated that IORT can be administered to patients who have locally advanced NSCLC and head and neck cancer, in the context of aggressive combined modality therapy, and is generally well tolerated. Long-term efficacy and benefit can only be determined in the setting of carefully designed clinical trials. (See the article by Thomas and Merrick elsewhere in this issue for further discussion of this topic.) Several relatively small, single-institution pilot studies exploring the utility and benefit of IORT for locally advanced upper aerodigestive tract cancers have been conducted. Clear conclusions have been difficult to determine because of the mixing of disease stages, varying degrees and completeness of surgical resection, varying radiation doses, different schemas, and other factors. Yet, given the major morbidity and mortality associated with locally recurrent lung cancer, methods of improving local control need to be pursued and refined. Encouraging preliminary data suggest that IOERT can be safely administered and may benefit local control. Based on several centers' expertise in the combined modality treatment of locally advanced lung cancer and familiarity with IORT, the UCSF Thoracic Oncology Program has proposed a multicenter phase 2 study incorporating IORT in a combined multimodality treatment schema for patients who have completely resected locally advanced stage IIIA and IIIB NSCLC (nonpleural effusion, non-N3) (Fig. 1). It is hoped that this study will commence in the upcoming year.     

Intraoperative Radiation Therapy for Locally Advanced or Locally Recurrent Rectal Cancer

Colorectal cancer is a major cause of morbidity and mortality across the world. Although surgery alone is very effective for patients with early stage disease, patients with more advanced disease required a combined modality approach. Standard doses of radiation therapy are usually ineffective in controlling localized disease that cannot be widely resected. Radiation dose escalation with intraoperative radiation therapy (IORT) has been investigated for many years as a component of a trimodality strategy in patients at high risk for local recurrence. This paper reviews the evidence supporting inclusion of IORT in addition to external beam radiation, surgery, and chemotherapy in patients with very locally advanced primary rectal cancer and patients with locally advanced recurrent rectal cancer.     

Complications of intraoperative radiation therapy

The ability to demonstrate an improvement in therapeutic ratio is critical in assessing new treatment modalities; an evaluation of treatment complications is essential for this purpose. We have studied the severe complications occurring after treatment with intraoperative radiation therapy (IORT) in patients with locally advanced carcinoma of the rectum. Four groups of patients were compared: Group 1 (80 patients) had treatment with surgery alone for mobile and resectable tumors; Group 2 (23 patients) had treatment with high dose preoperative irradiation followed by surgical resection for tumors which were fixed to adjacent structures and initially unresectable for cure; Group 3 (24 patients, primary disease) and Group 4 (17 patients, locally recurrent disease) had locally advanced tumors as in Group 2 but were treated with IORT after preoperative irradiation and attempted surgical resection. All but 3 complications occurred within one year of therapy. Severe complications were seen in 16% of patients in Group 1, 35% in Group 2, 21% in Group 3 and 47% in Group 4 (32% in Groups 3 and 4 combined). There was a statistically insignificant increase (p = .10) in the complication rate in all irradiated patients (locally advanced tumors) compared to surgery alone (clinically mobile tumors). These data indicate no increase in severe complications with the use of IORT. If the ongoing studies continue to show improved local control with the use of IORT, expanded use of this modality may be warranted.     

The role of intraoperative radiotherapy in pancreatic cancer

In single-institution studies, IORT at appropriate doses seems to safely improve local control in patients who have locally advanced pancreatic cancer, compared with historical controls. IORT also has been a component of adjuvant treatment programs that have led to excellent local control in resected patients. When considering the use of IORT, it is essential to have an understanding of the physical characteristics of the electron beam and how it can differ with the use of flat and beveled applicators. Although apparent improvement in local control with the use of IORT seems to have produced some improvement in median survival rates, high rates of distant failure continues to prevent a significant improvement in long-term survival. Because effective local control in patients with unresectable pancreatic cancer is a prerequisite to the development of curative therapies, the development of improved systemic therapies in patients with locally advanced pancreatic cancer will likely make local therapies such as the use of IORT even more important in the future.     

The role of intraoperative radiation therapy (IORT) in the treatment of locally advanced gynecologic malignancies

The prognosis in women with locally advanced primary or recurrent gynecologic malignancies is rather poor. Doses of external beam radiation necessary to treat gross or microscopic recurrence among patients surgically treated or previously irradiated exceed what is tolerated by normal structures. In this group of patients, intraoperative radiation therapy (IORT) can be utilized to maximize local tumor control, minimizing the radiation exposure of dose-limiting surrounding structures. Review of the available literature indicates that IORT may improve long-term local control and overall survival in women with pelvic sidewall and/or para-aortic nodal recurrence. The most encouraging results have been reported in the cases of microscopic residual disease, following surgical debulking.     

Importance of intraoperative radiation therapy in the treatment of soft tissue sarcoma: data at hand

Intraoperative radiation therapy (IORT) delivers a high single-dose radiation during surgery, which in combination with perioperative conventional fractionated external beam radiation therapy enables increase the total dose to the tumor bed without increasing normal tissue morbidity. Therefore, it can improve local tumor control. Numerous clinical studies have proved the feasibility and efficacy of IORT in patients with sarcomas of the trunk and extremities, as well as retroperitoneal tumors. In this publication, theoretical and practical essentials regarding the utilization of IORT in the multimodal treatment of sarcoma will be discussed.     

Orthovoltage intraoperative radiotherapy: a new look at an old idea

A 300 kvp orthovoltage machine has been permanently installed in an operating room for delivering intraoperative radiation therapy (IORT). A historical review of orthovoltage IORT and our present approach are described. The preliminary experience with 38 patients treated with orthovoltage IORT indicates that this technique is feasible, has low acute morbidity, and can be useful for palliation. "Radical" radiation therapy consisting of IORT "boost" treatment combined with external beam was used in 24 patients with primary or recurrent cancer. Local failure in 27 patients treated with IORT +/- external beam radiation therapy was 56%, but varied from 11% (1/9) for patients with resected disease to 78% (14/18) for patients with unresected disease. Complications occurred in nine patients (24%) and have been acceptable. There are 17 patients alive and six are NED, with follow-up of 4-18 months. There appears to be a role for orthovoltage IORT especially when combined with surgical resection for local control of advanced cancer arising in the abdomen where the use of high doses of external radiation therapy are hazardous.     

Intraoperative electron beam radiation therapy for primary locally advanced rectal and rectosigmoid carcinoma

To improve local control and survival in patients with primary locally advanced rectal and rectosigmoid carcinoma, intraoperative electron beam radiation therapy (IORT) has been used with a combination of moderate- to high-dose preoperative radiation therapy and surgical resection. Sixty-five patients underwent resection with the intention of using IORT if areas at high risk for local recurrence were apparent at surgery. For 20 patients undergoing complete resection with IORT, the 5-year actuarial local control and disease-free survival (DFS) was 88% and 53%, respectively. The results for 22 patients with pathologically documented residual carcinoma were less satisfactory with a 5-year actuarial local control and DFS of 60% and 32%, respectively. In this latter group, local control and DFS correlated with the extent of residual disease: patients with only microscopic disease had a 5-year actuarial local control and DFS of 69% and 47%, respectively, whereas for patients with macroscopic disease, these figures were 50% and 17%, respectively. For 18 patients undergoing complete resection without IORT or additional postoperative radiation therapy, the 5-year actuarial local control and DFS was 67% and 53%, respectively. Because local failure will occur in at least 30% of patients undergoing partial resection with or without IORT as well as patients undergoing complete resection of advanced tumors without IORT, additional postoperative radiation therapy should be considered.     

High-dose-rate intraoperative irradiation: current status and future directions

Intraoperative irradiation (IORT) refers to the delivery of a single high dose of radiation therapy at the time of surgery when the tumor bed can be precisely defined and adjacent normal tissue maximally protected. It can be effectively delivered using either electrons (IOERT) or photons produced from a high-dose-rate gamma emitting radioisotope (HDR-IORT) and has been explored primarily for locally advanced or recurrent tumors at high risk for local failure despite extensive resection and full dose external beam radiation. With coordinated multidisciplinary interaction, IORT can be integrated in a combined-modality setting without undue additional toxicity. The purpose of this review will be to summarize the growing HDR-IORT experience in the treatment of various cancers, to compare its efficacy and toxicity vis a vis the IOERT data, and to discuss future trials as well as new areas of potential application.     

Treatment of locally advanced rectal cancer with external beam radiation, surgical resection, and intraoperative radiation therapy

To try to improve the local control and survival of patients with locally advanced rectal cancer we have used a combination of high-dose pre-operative radiation therapy to 5,040 cGy followed by surgical resection and intraoperative electron beam radiation therapy (IORT) when there was visible or palpable residual disease, microscopically positive surgical margins, or persisting tumor adherence. A total of 75 patients were taken to surgery for resection +/- IORT who did not have distant metastases. Of the 49 patients with primary tumors, 11 did not have IORT as the tumor was thought to be completely resected. Of these 11, there were two local recurrences and a 3-year survival of 71%. Thirty-six patients with primary tumors had resection (20 complete, 16 partial) plus IORT, with a 3-year survival of 58% and three local failures. Twenty-six additional patients were treated for locally advanced recurrence of whom four could not receive IORT because of pelvic size or the extent of tumor. Of the 22 who received IORT, 7/9 with complete resection, 2/8 with partial resection, and 1/5 with no resection had local control with an overall 3-year actuarial survival of 32%. The local control and survival results in the primary tumors appear favorable compared to other series in the literature and suggest benefit to the use of IORT. For patients treated for local recurrence, local control and long-term survival can be obtained, but the results are not as encouraging as for the primary tumors.     

The influence of surgical margins on advanced cancer treated with intraoperative radiation therapy (IORT) and surgical resection

Intraoperative radiation therapy (IORT) has been used successfully in the treatment of malignancies, alone and as an adjunct to surgical resection. This study examined a single institution's experience with combined IORT and surgical resection in the treatment of advanced cancer. The records of 41 consecutive patients undergoing intraoperative radiation therapy (IORT) at the Fox Chase Cancer Center, from My 1987 through March 1990, were retrospectively reviewed. All patients had locally advanced disease, of whom 73% had failed previous multimodality therapy and 44% had undergone prior radiation therapy (XRT). The 2-year actuarial survival for the entire cohort was 72%. Disease-free survival was 47% at 1 year and 5% at 2 years. The only important prognostic factor predicting outcome was status of the surgical margin. Positive surgical margins decreased the 2-year actuarial survival from 100% to 59%, and increased the local failure rate from 21% to 52%. Margin status had no effect on the later development of metastatic diseae. Higher IORT doses, field sizes >7 cm, and multiple IORT fields were used for larger tumors and larger amounts of residual disease. These parameters alone did not correlate with improved local control. This analysis suggests the usefulness of aggressive surgical resection with IORT in extending survival for locally advanced or recurrent cancer. Negative margin status is the best predictor of a favorable outcome and should be used to select patients who may benefit from IORT. The use of radiation sensitizing agents should be explored in patients with positive margins, since in-field failure continues to be the major pattern of failure. IORT in conjunction with aggressive surgical resection should continue to be studied in prospective randomized clinical trials. © 1993 Wiley-Liss, Inc.     

Intraoperative radiotherapy: current thinking.

Intraoperative radiotherapy (IORT) refers to the delivery of irradiation at surgery. A large single dose of irradiation is delivered to a surgically defined area, while uninvolved and dose-limiting tissues are displaced, the final goal of IORT being enhanced locoregional tumour control. IORT is used in most modern protocol studies as a boost radiation component of multidisciplinary treatment approaches. More recently, high activity radiation sources or mobile operating room treatment machines are used to facilitate the IORT procedure. Clinical experiences have shown that IORT may improve local control and disease-free survival, especially when used in adjuvant setting, combined with external beam irradiation in some neoplasms such as cancer of the stomach, pancreas, colorectum, and soft tissue sarcoma. Copyright Harcourt Publishers Limited.     

Research opportunities in intraoperative radiation therapy: the next decade 2013–2023

The reality of intraoperative radiation therapy (IORT) practice is consistent with an efficient and highly precise radiation therapy technique to safely boost areas at risk for local recurrence. Long-term clinical experience has shown that IORT-containing multi-modality regimens appear to improve local disease control, if not survival in many diseases. Research with IORT is a multidisciplinary scenario that covers knowledge from radiation beam adapted development to advance molecular biology for bio-predictability of outcome. The technical parameters employed in IORT procedures are important information to be recorded for quality assurance and clinical results analysis. In addition, specific treatment planning systems for IORT procedures are available, to help in the treatment decision-making process. A systematic revision of opportunities for research and innovation in IORT is reported including radiation beam modulation, delivery, dosimetry and planning; infrastructure and treatment factors; experimental and clinical radiobiology; clinical trials, innovation and translational research development.     

History, preliminary results, complications, and future prospects of intraoperative radiotherapy

Intraoperative electron beam radiotherapy (IORT) is a new combined modality therapy in the treatment of cancer. IORT is delivered during a surgical procedure to a tumor or tumor bed and areas of possible local regional spread, with the ability to shield or physically move normal tissues and organs out of the treatment volume. IORT is feasible for various intraabdominal, retroperitoneal, pelvic, and other malignancies. It is possible to increase the total radiation dose, thereby improving the therapeutic ratio; a better local control without an increasing morbidity. Although the optimum use of IORT is still unknown, it is believed that its greatest value is in combination with maximal surgical resection of the tumor with or without external beam radiotherapy (EBRT). IORT is still an experimental treatment modality combining surgery, EBRT, and if necessary, chemotherapy. Because IORT is an expensive treatment method, it is important to determine which method is the best and most convenient for the patient. The answer can be given only when prospective, randomized clinical IORT trials and cost-effectiveness studies are initiated.     

Local tumor control by intra-operative radiotherapy (IORT): a pilot experience

Patients with locally advanced disease, considered incurable by conventional therapeutic options, were treated, if possible, with surgical resection, and intra-operative radiotherapy (IORT) with or without external beam radiotherapy (EBRT), with the aim of improving local control of disease. Twelve patients were selected for IORT and eight patients were subsequently submitted to IORT in order to achieve local control. There were no IORT related complications, and local tumor control was achieved in all cases with a median follow-up of 22 months. IORT is a new and experimental treatment modality with a potential advantage over conventional radiotherapy.     

A study of radiotherapy modalities combined with continuous 5-FU infusion for locally advanced gastrointestinal malignancies.

AIM: We describe the feasibility of combining infusional 5-fluorouracil (5-FU) with intraoperative radiation therapy (IORT). METHODS: Patients with surgically resectable locally advanced gastrointestinal cancers were treated concurrently during surgery with IORT and a 72 h infusion of 5-FU. Patients without previous external beam radiation therapy (EBRT) were subsequently treated with EBRT (40-50Gy) concurrent with a 21-day continuous infusion of 5-FU. Pancreatic, gastric, duodenal, ampullary, recurrent colorectal, and recurrent anal cancer were included. RESULTS: During IORT/5-FU, no chemotherapy-related grade III or IV hematologic or gastrointestinal toxicity was noted. Post-surgical recovery or wound healing was not affected. One of nine patients who received post-operative radiation required a treatment break. During follow-up, there were more complications in patients with pelvic tumours, especially those with previous radiation. Nine patients have had local and/or local regional recurrences, two of these in the IORT field. CONCLUSIONS: Treatment with a combination of IORT and 5-FU followed by EBRT and 5-FU is feasible. However, long-term complications may be increased in previously irradiated recurrent pelvic tumours.     

Intraoperative radiation therapy in the management of gynecologic and genitourinary malignancies

Women with locally advanced primary or recurrent gynecologic malignancies have a poor prognosis. The doses of external radiation necessary to treat gross or microscopic recurrent disease in patients previously irradiated exceed the doses tolerated by normal tissue [1,3-5]. IORT has been added to the treatment armamentarium in this group of patients to maximize local control and minimize the radiation exposure to dose-limiting surrounding structures. In addition, IORT may improve the long-term local control and the overall survival rates in women with pelvic sidewall or para-aortic nodal recurrence [1,4,5]. The most encouraging results are seen in cases of microscopic residual disease following surgical debulking [4,6]. In gynecologic malignancies, IORT has served to reiterate the importance of optimal surgical resection. Higher 5-year disease-free and overall survival rates have been documented in women who have microscopic residual disease, compared with those who have gross residual disease [1,3-6]. IORT in the management of GU malignancies has not been used extensively. In RCC, where surgery alone often results in suboptimal treatment results, IORT seems to be well tolerated and controls local disease [2,27,29,30]. Because of the chemoresistant nature of RCC, IORT may play an important role in the future in the management of locally advanced and recurrent RCC. In bladder cancer, IORT had been used in combination with chemotherapy and EBRT, as part of bladder-sparing protocols. The data suggest that IORT in this patient population is also well tolerated, and may become more widely used as less radical surgical procedures gain clinical importance. IORT in the treatment of prostate and testicular cancers has not been used frequently, given the highly efficacious treatment modalities currently available to treat these malignancies. A review of institutional experiences with IORT may allow the establishment of guidelines for patient selection. These criteria, in turn, may be useful in the design of clinical trials. The construction, execution, and evaluation of clinical trials are mandatory to adequately assess the role of IORT in the treatment of patients with gynecologic and GU malignancies.